As part of our program of research on early markers of Alzheimers disease, we are performing serial magnetic resonance imaging (MRI), including measures of vascular changes, positron emission tomography (PET), and neuropsychological assessments in participants from the Baltimore Longitudinal Study of Aging (BLSA) to investigate the neurobiological basis of memory change and cognitive impairment. These evaluations allow us to examine changes in brain structure and function which may be early preclinical predictors of cognitive change and impairment, including Alzheimer's disease (AD). Longitudinal neuroimaging evaluations of BLSA participants began in 1994 with approximately 160 individuals aged 55-85 at enrollment. In 2009, we expanded MRI assessments to more than 1000 individuals (with 645 receiving 2 or more scans) and cognitive assessments. For a subsample aged 55 and older, we performed PET measurements of cerebral blood flow, followed by a PET scan using 11-C-Pittsburgh Compound B (PiB) to measure in vivo amyloid deposition in 225 individuals to date. We initiated Tau PET (AV-1451) studies of BLSA participants receiving PET amyloid scans (separate annual report), with more than 100 individuals receiving Tau PET to date. Our progress includes continued acquisition of neuroimaging assessments, analysis of existing data and methods development. We use neuroimaging tools to investigate modulators of cognitive and brain changes, including sex differences in cognitive and brain aging, genetic, metabolic, and inflammatory risk factors. Early detection of accelerated brain changes during the preclinical or asymptomatic stages of disease will be critical in identifying individuals likely to benefit from interventions if a successful treatment for prevention or delaying onset of AD is available. Key publications are highlighted in the following sections. In Armstrong et al. (NBA 2019), we investigated predictors of neurodegeneration, measured by MRI-based volume loss, in older BLSA participants who remained cognitively normal (n=623) compared with individuals who subsequently developed cognitive impairment (SI, N=65). Importantly, all individuals were cognitively normal at all imaging assessments. We performed mixed-effects regression to assess differences in rates of regional brain volume loss between SI and cognitively normal individuals and to examine the associations of AD risk factors (age, APOE e4 carrier status, diabetes, hypertension, obesity, current smoking, and elevated cholesterol) with regional volume change among the overall sample and by diagnostic status. SI compared with cognitively stable individuals showed greater longitudinal tissue loss in a number of medial temporal lobe structures, including amygdala, hippocampus, entorhinal cortex and parahippocampal gyrus. Older age, APOE e4 carrier status, hypertension, and HDL cholesterol were predictors of greater longitudinal volumetric change. Among SI participants only, hypertension, obesity, and APOE e4 carrier status were associated with greater declines in selected brain regions. Thus, SI individuals in the preclinical asymptomatic stage of AD show early medial temporal lobe volume loss and are vulnerable to risk factors that have either a protective or null effect in those who remain cognitively normal. In a second paper (Armstrong et al., NBA, 2019), we evaluated sex differences in MRI-based volume loss and differences in predictors of this neurodegeneration in cognitively healthy older adults. Mixed-effects regression was used to compare regional brain volume trajectories of 295 male and 328 female BLSA participants, aged 55-92 years, with up to 20 years of follow-up and to assess sex differences in the associations of age, hypertension, obesity, APOE e4 carrier status, and high-density lipoprotein cholesterol with regional brain volume trajectories. For both sexes, older age was associated with steeper volumetric declines, with males showing greater rates of tissue loss than women in many brain regions. In males, hypertension and higher high-density lipoprotein cholesterol were protective against volume loss in the hippocampus, entorhinal cortex, and parahippocampal gyrus. In females, hypertension was associated with steeper volumetric decline in gray matter, and obesity was protective against volume loss in temporal gray matter. In sum, we observed sex differences in rates of tissue loss with aging, as well as sex differences in predictors of volume change. We also investigated effects of age, sex, APOE genotype and vascular risk factors on white matter (WM) microstructure, measured with diffusion tensor imaging (DTI; Williams et al., NeuroImage, 2019). The study included 665 cognitively normal BLSA participants with a total of 1384 DTI scans. WM microstructure was assessed by fractional anisotropy (FA) and mean diffusivity (MD). Linear mixed effects models assessed the association of baseline vascular burden, APOE e4 genotpye and sex on baseline and on rates of change of FA and MD, while controlling for age, race, and scanner type. Higher baseline vascular burden was associated with lower FA and higher MD in many WM structures including association, commissural, and projection fibers. Higher baseline vascular burden was also associated with greater longitudinal decline in FA in the hippocampal part of the cingulum and the fornix (crus)/stria terminalis and splenium of the corpus callosum, and with greater increases in MD in the splenium of the corpus callosum. APOE e4 carriers did not differ from non-carriers in baseline DTI metrics but had greater decline in FA in the genu and splenium of the corpus callosum. Men had higher FA and lower MD than women in multiple WM regions at baseline but showed greater increase in MD in the genu of the corpus callosum. Women showed greater decreases over time in FA in the gyrus part of the cingulum, compared to men. Our findings show that modifiable vascular risk factors have a negative impact on white matter microstructure and are associated with faster microstructural deterioration of temporal WM regions and the splenium of the corpus callosum in cognitively normal adults. Reducing vascular burden in aging could modify the rate of WM deterioration and could decrease age-related cognitive decline and impairment. In a methodological paper (Bilgel et al., JCBFM 2019), we investigated whether surrogates of neuronal activity, measured by regional cerebral blood flow (rCBF), can be estimated from dynamic amyloid PET imaging. Using data for 149 BLSA participants (345 visits), we assessed whether the average of early amyloid frames (EA) and R1 computed from dynamic PiB PET can serve as surrogates of rCBF computed from 15O-H2O-PET. R1 had the highest longitudinal test-retest reliability. Interquartile range (IQR) of cross-sectional Pearson correlations with rCBF was 0.60-0.72 for EA and 0.63-0.72 for R1. Correlations between rates of change were lower. Values in an Alzheimer's metabolic signature meta-ROI (region-of-interest) were negatively associated with age and exhibited longitudinal declines for each PET measure. In age-adjusted analyses, meta-ROI rCBF and R1 were lower among amyloid+ individuals; EA and R1 were lower among males. Regional PiB-based measures, in particular R1, can be suitable surrogates of rCBF, perhaps obviating the need for a separate scan to measure neuronal activity and reducing patient burden, radioactivity exposure, and cost. Data generated by this project are also used by many intramural and extramural collaborators for methods development and in studies of the neural underpinnings of motor function, energetics, sleep and a variety of sensorimotor functions.